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Related Experiment Videos

P-glycoprotein function involves conformational transitions detectable by differential immunoreactivity

E B Mechetner1, B Schott, B S Morse

  • 1Department of Molecular Genetics, University of Illinois, Chicago 60607-7170, USA.

Proceedings of the National Academy of Sciences of the United States of America
|December 16, 1997
PubMed
Summary
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The MDR1 P-glycoprotein (Pgp) antibody UIC2 inhibits drug efflux by trapping Pgp in specific conformations. This trapping mechanism is linked to ATP hydrolysis stages, offering insights into Pgp function and antibody-based inhibition strategies.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • The MDR1 P-glycoprotein (Pgp) is an ATP-binding cassette transporter involved in effluxing lipophilic compounds, including anti-cancer drugs.
  • Pgp's function is critical in multidrug resistance, impacting cancer therapy efficacy.
  • Understanding Pgp conformational changes is key to developing strategies to overcome drug resistance.

Purpose of the Study:

  • To investigate the mechanism by which mAb UIC2 inhibits Pgp-mediated drug efflux.
  • To elucidate the relationship between Pgp conformation, ATP hydrolysis, and antibody binding.
  • To explore the potential of antibody-mediated trapping in transient Pgp conformations.

Main Methods:

  • Utilized mAb UIC2, which targets the extracellular domain of Pgp.

Related Experiment Videos

  • Assessed UIC2 reactivity under conditions affecting Pgp transport and ATP hydrolysis (e.g., addition of substrates, ATP depletion).
  • Employed Pgp mutants with inactivated nucleotide-binding domains (NBDs) to probe conformational states.

    • Main Results:

    • UIC2 reactivity increased with Pgp-transported compounds or ATP depletion in wild-type and single-NBD mutants, but not in double-NBD mutants.
    • Binding of UIC2 to Pgp mutated in both NBDs was insensitive to transport substrates or ATP depletion.
    • These findings suggest distinct Pgp conformations exist during transport-associated ATP hydrolysis.

    Conclusions:

    • Antibody-mediated inhibition of Pgp may occur by trapping the transporter in transient conformations.
    • Different Pgp conformations are associated with various stages of ATP hydrolysis.
    • This study provides a mechanistic basis for antibody-based modulation of Pgp activity.